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Patrick Trévidic - One of the best experts on this subject based on the ideXlab platform.
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Primary Lymphedema French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins)
Orphanet Journal of Rare Diseases, 2021Co-Authors: Stéphane Vignes, Juliette Albuisson, Laurence Champion, Joël Constans, Valérie Tauveron, Julie Malloizel, Isabelle Quéré, Laura Simon, Maria Arrault, Patrick TrévidicAbstract:Primary Lymphedema is a rare chronic pathology associated with constitutional abnormalities of the lymphatic system. The objective of this French National Diagnosis and Care Protocol (Protocole National de Diagnostic et de Soins; PNDS), based on a critical literature review and multidisciplinary expert consensus, is to provide health professionals with an explanation of the optimal management and care of patients with Primary Lymphedema. This PNDS, written by consultants at the French National Referral Center for Primary Lymphedema, was published in 2019 ( https://has-sante.fr/upload/docs/application/pdf/2019-02/pnds_lymphoedeme_primaire_final_has.pdf ). Primary Lymphedema can be isolated or syndromic (whose manifestations are more complex with a group of symptoms) and mainly affects the lower limbs, or, much more rarely, upper limbs or external genitalia. Women are more frequently affected than men, preferentially young. The diagnosis is clinical, associating mild or non-pitting edema and skin thickening, as confirmed by the Stemmer’s sign (impossibility to pinch the skin on the dorsal side or the base of the second toe), which is pathognomonic of Lymphedema. Limb lymphoscintigraphy is useful to confirm the diagnosis. Other causes of swelling or edema of the lower limbs must be ruled out, such as lipedema. The main acute Lymphedema complication is cellulitis (erysipelas). Functional and psychological repercussions can be major, deteriorating the patient’s quality of life. Treatment aims to prevent those complications, reduce the volume with low-stretch bandages, then stabilize it over the long term by exercises and wearing a compression garment. Patient education (or parents of a child) is essential to improve observance.
Stéphane Vignes - One of the best experts on this subject based on the ideXlab platform.
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Primary Lymphedema French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins)
Orphanet Journal of Rare Diseases, 2021Co-Authors: Stéphane Vignes, Juliette Albuisson, Laurence Champion, Joël Constans, Valérie Tauveron, Julie Malloizel, Isabelle Quéré, Laura Simon, Maria Arrault, Patrick TrévidicAbstract:Primary Lymphedema is a rare chronic pathology associated with constitutional abnormalities of the lymphatic system. The objective of this French National Diagnosis and Care Protocol (Protocole National de Diagnostic et de Soins; PNDS), based on a critical literature review and multidisciplinary expert consensus, is to provide health professionals with an explanation of the optimal management and care of patients with Primary Lymphedema. This PNDS, written by consultants at the French National Referral Center for Primary Lymphedema, was published in 2019 ( https://has-sante.fr/upload/docs/application/pdf/2019-02/pnds_lymphoedeme_primaire_final_has.pdf ). Primary Lymphedema can be isolated or syndromic (whose manifestations are more complex with a group of symptoms) and mainly affects the lower limbs, or, much more rarely, upper limbs or external genitalia. Women are more frequently affected than men, preferentially young. The diagnosis is clinical, associating mild or non-pitting edema and skin thickening, as confirmed by the Stemmer’s sign (impossibility to pinch the skin on the dorsal side or the base of the second toe), which is pathognomonic of Lymphedema. Limb lymphoscintigraphy is useful to confirm the diagnosis. Other causes of swelling or edema of the lower limbs must be ruled out, such as lipedema. The main acute Lymphedema complication is cellulitis (erysipelas). Functional and psychological repercussions can be major, deteriorating the patient’s quality of life. Treatment aims to prevent those complications, reduce the volume with low-stretch bandages, then stabilize it over the long term by exercises and wearing a compression garment. Patient education (or parents of a child) is essential to improve observance.
Arin K Greene - One of the best experts on this subject based on the ideXlab platform.
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ephb4 mutation causes adult and adolescent onset Primary Lymphedema
American Journal of Medical Genetics Part A, 2021Co-Authors: Arin K Greene, Pascal Brouillard, Christopher L Sudduth, Patrick Smits, Dennis J Konczyk, Miikka VikkulaAbstract:Primary Lymphedema results from the anomalous development of the lymphatic system and typically presents during infancy, childhood, or adolescence. Adult-onset Primary Lymphedema is rare and mutations associated with this condition have not been identified. The purpose of this investigation was to search for variants that cause adult-onset Primary Lymphedema. We discovered an autosomal dominant EPHB4 mutation in a patient who developed unilateral leg Lymphedema at age 39 years; the same mutation affected his son who presented with the disease at 14 years of age.
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Primary Lymphedema update on genetic basis and management
Advances in wound care, 2021Co-Authors: Christopher L Sudduth, Arin K GreeneAbstract:Significance: Primary Lymphedema is a chronic condition without a cure. The lower extremities are more commonly affected than the arms or genitalia. The disease can be syndromic. Morbidity includes decreased self-esteem, infections, and reduced function of the area. Recent Advances: Several mutations can cause Lymphedema, and new variants continue to be elucidated. A critical determinant that predicts the natural history and morbidity of Lymphedema is the patient's body mass index (BMI). Individuals who maintain an active lifestyle with a normal BMI generally have less severe disease compared to subjects who are obese. Because other causes of lower extremity enlargement can be confused with Lymphedema, definitive diagnosis requires lymphoscintigraphy. Critical Issues: Most patients with Primary Lymphedema are satisfactorily managed with compression regimens, exercise, and maintenance of a normal body weight. Suction-assisted lipectomy is our preferred operative intervention for symptomatic patients who have failed conservative therapy. Suction-assisted lipectomy effectively removes excess subcutaneous fibro-adipose tissue and can improve underlying lymphatic function. Future Directions: Many patients with Primary Lymphedema do not have an identifiable mutation and thus novel variants will be identified. The mechanisms by which mutations cause Lymphedema continue to be studied. In the future, drug therapy for the disease may be developed.
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adult onset Primary Lymphedema a clinical lymphoscintigraphic study of 26 patients
Lymphatic Research and Biology, 2019Co-Authors: Jeremy A Goss, Reid A Maclellan, Arin K GreeneAbstract:Background: Primary Lymphedema results from the anomalous development of the lymphatic system that typically presents during infancy, childhood, or adolescence. Adult-onset Primary Lymphedema is rare and has not been studied. The purpose of this investigation was to characterize patients with Primary Lymphedema that developed after the pediatric time period to better understand the condition. Study Design: Patients treated in our Lymphedema Program between 2009 and 2018 were reviewed. Diagnosis was determined based on history, physical examination, and imaging studies. Patients with Primary Lymphedema developing in adulthood (>21 years) were identified. Sex, age of onset, location, severity, morbidity, family history, associated features, and lymphoscintigraphy findings were documented. Results: Twenty-six patients (10%) of 259 with Primary Lymphedema developed the disease during adulthood. Sixteen individuals were female, and the disease occurred at an average age of 40 years (range, 24-72). It affected the lower extremity (85%) (unilateral 82%, bilateral 18%) or upper limb (15%) (unilateral 80%, bilateral 20%). Twenty-seven percent of patients suffered infections. Ninety-five percent of lymphoscintigrams exhibited delayed transit of radiolabeled tracer and 73% showed dermal backflow. None of the patients had systemic lymphatic involvement or associated vascular anomalies. One patient had a family history of Lymphedema. Conclusions: Adult-onset Primary Lymphedema is typically unilateral, affects the lower extremity, and is not associated with systemic lymphatic anomalies; hereditary transmission is rare. Because adult-onset Lymphedema is much less common than the pediatric condition, the disease should be confirmed with lymphoscintigraphy. Imaging of the axillary or inguinal nodes is also considered to rule out a lesion causing secondary Lymphedema.
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lymphoscintigraphic evaluation of systemic tracer uptake in patients with Primary Lymphedema
Annals of Plastic Surgery, 2019Co-Authors: Jeremy A Goss, Reid A Maclellan, Arin K GreeneAbstract:BackgroundLymphoscintigraphy is used to confirm the diagnosis of Lymphedema. One end point for the test is to ensure a patent thoracic duct by uptake of tracer in the organs. The purpose of this study was to evaluate transit of radiolabeled colloid to the organs to gain insight into the etiopathophy
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Primary Lymphedema of the upper extremities clinical and lymphoscintigraphic features in 23 patients
Lymphatic Research and Biology, 2019Co-Authors: Jeremy A Goss, Reid A Maclellan, Arin K GreeneAbstract:Abstract Background: Primary idiopathic Lymphedema is an uncommon condition that typically affects the lower extremities. Patients have a malformed lymphatic system that causes subcutaneous fluid a...
Alfred Bollinger - One of the best experts on this subject based on the ideXlab platform.
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flow velocity of cutaneous lymphatic capillaries in patients with Primary Lymphedema
International Journal of Microcirculation, 1997Co-Authors: M Fischer, Alfred Bollinger, U Costanzo, Ulrich Hoffmann, Ulrich K. FranzeckAbstract:For the first time measurements of lymph flow velocities in cutaneous microlymphatics of patients with Lymphedema were performed and compared with healthy subjects. Flow velocity in single lymphatic skin capillaries was measured using fluorescence video microscopy after subepidermal microinjection of FITC-dextran 150,000 in 15 healthy volunteers and 16 patients with Primary Lymphedema. Initial filling of the lymphatic capillary network was fast with significantly higher mean velocities in patients with Primary Lymphedema than in healthy controls (890 +/- 43 vs. 550 +/- 390 microns/s, p < 0.05). The resting velocities were not significantly different between controls and patients (10.3 +/- 4.1 vs. 16.6 +/- 13.9 microns). In 12 out of the 16 Lymphedema patients cutaneous backflow of the fluorescent contrast medium from deeper invisible lymphatics was observed. In 4 of these patients rhythmic reflux with a mean frequency of 1.4 +/- 0.5 cycles/min was measured by video densitometry in microlymphatics with a significantly (p < 0.01) enhanced diameter. Mean flow velocity (Vp) in these precollectors was significantly increased compared to the resting velocities (p < 0.01). On the basis of these results the hypothesis is advanced that rhythmic cutaneous backflow originates from intrinsic contractions of deeper lymph collector segments and is transmitted to the superficial microlymphatics through incompetent connecting channels. This newly recognized mechanism appears to be an important factor for the pathophysiology of Lymphedema.
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fluctuation of skin lymphatic capillary pressure in controls and in patients with Primary Lymphedema
Journal of Vascular Research, 1994Co-Authors: J Dorfflermelly, I Herrig, Marc Schiesser, Ulrich K. Franzeck, Alfred BollingerAbstract:The microlymphatic pressure was monitored by using the servo-nulling technique at the forefoot skin in 24 healthy volunteers (number of capillaries studied: 97) and in 27 patients with Primary Lymphedema (capillary number: 67). The lymphatic capillaries were stained by fluorescence microlymphography with fluorescein isothiocyanate-dextran 150 and cannulated using glass needles with a diameter between 7 and 9 µm. The lymphatic capillary hypertension described recently in Primary Lymphedema was confirmed in this series (mean pressure of controls 6.7 ± 3.8 and, of patients 12.8 ± 5.9 mm Hg; p
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lymphatic capillary pressure in patients with Primary Lymphedema
Microvascular Research, 1993Co-Authors: Beatrice R Zauggvesti, J Dorfflermelly, Ulrich K. Franzeck, Michael Spiegel, Alfred BollingerAbstract:Flow and pressure dynamics in minute human lymphatics are unexplored. Lymphatic capillary pressure was measured by the servo-nulling technique at the foot dorsum of 14 patients with Primary Lymphedema and 15 healthy controls. Glass micropipettes (7-9 μm) were inserted under microscopic control into lymphatic microvessels previously stained by fluorescence microlymphography (FITC-Dextran 150,000). Mean lymphatic capillary pressure was 7.9 ± 3.4 mm Hg in the controls and 15.0 ± 5.1 mm Hg in the patients. The difference was significant at the P < 0.001 level. In about half of the patients and control subjects studied pressure fluctuated by more than 3 mm Hg. The mean intralymphatic pressure of Lymphedema patients was slightly below mean interstitial pressure measured by J. T. Christensen, N. J. Shaw, M. M. Hamas and H. K. Al Hassan (1985, Microcirc., Endothelium, Lymphatics2, 267-384) (17.9 mm Hg) in lower leg Lymphedema. Microlymphatic hypertension present in patients with Primary Lymphedema is probably an important factor for edema formation.
Miikka Vikkula - One of the best experts on this subject based on the ideXlab platform.
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ephb4 mutation causes adult and adolescent onset Primary Lymphedema
American Journal of Medical Genetics Part A, 2021Co-Authors: Arin K Greene, Pascal Brouillard, Christopher L Sudduth, Patrick Smits, Dennis J Konczyk, Miikka VikkulaAbstract:Primary Lymphedema results from the anomalous development of the lymphatic system and typically presents during infancy, childhood, or adolescence. Adult-onset Primary Lymphedema is rare and mutations associated with this condition have not been identified. The purpose of this investigation was to search for variants that cause adult-onset Primary Lymphedema. We discovered an autosomal dominant EPHB4 mutation in a patient who developed unilateral leg Lymphedema at age 39 years; the same mutation affected his son who presented with the disease at 14 years of age.
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angiosarcoma arising from congenital Primary Lymphedema
Pediatric Dermatology, 2018Co-Authors: Pauline Janssens, Fanny Ballieux, Valerie Dekeuleneer, An Van Damme, Nicole Revencu, Philippe Clapuyt, Ingrid Ferreira, Pascal Brouillard, Miikka Vikkula, Liliane MarotAbstract:: We herein report the case of a 3-year-old girl with atypical congenital right upper limb Lymphedema who developed an angiosarcoma. Only a few cases have been reported following congenital form of Lymphedema and only 4 in such a young child. We also summarize all cases of angiosarcoma associated with congenital Lymphedema reported in the literature.
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incidence of cellulitis among children with Primary Lymphedema
The New England Journal of Medicine, 2018Co-Authors: I Quere, Nicolas Nagot, Miikka VikkulaAbstract:Cellulitis in Children with Lymphedema The incidence of cellulitis among 128 patients with Lymphedema was 4.2 episodes per 100 patient-years. In 29% of the cases, patients had a second episode, and...
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loss of adamts3 activity causes hennekam lymphangiectasia Lymphedema syndrome 3
Human Molecular Genetics, 2017Co-Authors: Pascal Brouillard, Laura Dupont, Raphael Helaers, Richard Coulie, George E Tiller, Joseph Peeden, Alain Colige, Miikka VikkulaAbstract:Primary Lymphedema is due to developmental and/or functional defects in the lymphatic system. It may affect any part of the body, with predominance for the lower extremities. Twenty-seven genes have already been linked to Primary Lymphedema, either isolated, or as part of a syndrome. The proteins that they encode are involved in VEGFR3 receptor signaling. They account for about one third of all Primary Lymphedema cases, underscoring the existence of additional genetic factors. We used whole-exome sequencing to investigate the underlying cause in a non-consanguineous family with two children affected by Lymphedema, lymphangiectasia and distinct facial features. We discovered bi-allelic missense mutations in ADAMTS3. Both were predicted to be highly damaging. These amino acid substitutions affect well-conserved residues in the prodomain and in the peptidase domain of ADAMTS3. In vitro, the mutant proteins were abnormally processed and sequestered within cells, which abolished proteolytic activation of pro-VEGFC. VEGFC processing is also affected by CCBE1 mutations that cause the Hennekam lymphangiectasia-Lymphedema syndrome syndrome type1. Our data identifies ADAMTS3 as a novel gene that can be mutated in individuals affected by the Hennekam syndrome. These patients have distinctive facial features similar to those with mutations in CCBE1. Our results corroborate the recent in vitro and murine data that suggest a close functional interaction between ADAMTS3 and CCBE1 in triggering VEGFR3 signaling, a cornerstone for the differentiation and function of lymphatic endothelial cells.
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genetics of lymphatic anomalies
Journal of Clinical Investigation, 2014Co-Authors: Pascal Brouillard, Laurence M Boon, Miikka VikkulaAbstract:Lymphatic anomalies include a variety of developmental and/or functional defects affecting the lymphatic vessels: sporadic and familial forms of Primary Lymphedema, secondary Lymphedema, chylothorax and chylous ascites, lymphatic malformations, and overgrowth syndromes with a lymphatic component. Germline mutations have been identified in at least 20 genes that encode proteins acting around VEGFR-3 signaling but also downstream of other tyrosine kinase receptors. These mutations exert their effects via the RAS/MAPK and the PI3K/AKT pathways and explain more than a quarter of the incidence of Primary Lymphedema, mostly of inherited forms. More common forms may also result from multigenic effects or post-zygotic mutations. Most of the corresponding murine knockouts are homozygous lethal, while heterozygotes are healthy, which suggests differences in human and murine physiology and the influence of other factors.